Vol. 292, Issue 1, 415-424, January 2000

Cellular and In Vivo Electrophysiological Effects of Dronedarone in Normal and Postmyocardial Infarcted Rats

Frank Aimond¹ , Lionel Beck¹ , Patrick Gautier, Ouafiya K. Chérif, Jean-Marc Davy, Paco Lorente, Dino Nisato and Guy Vassort

Institut National de la Santé et de la Recherche Médicale, Physiopathologie Cardiovasculaire, CHU Arnaud de Villeneuve (F.A., L.B., O.K.C., P.L., G.V.), Montpellier ; Service de Cardiologie CHU Arnaud de Villeneuve (J.-M.D.), Montpellier; and Sanofi Recherches (P.G., D.N.), Montpellier, France

We studied the effects of dronedarone (SR 33589) on the action potentials, membrane ionic currents, and arrhythmic activity in control rats and in rats after myocardial infarction, a model known to develop anomalous electrical activity. Dronedarone increased action potential duration in normal hearts. It had little effect on the action potentials that were already prolonged in the postmyocardial infarcted (PMI) rats. Particularly, dronedarone reduced the late sustained K⁺ current, I_K (or Isus) by 69%. Dronedarone induced only a tonic block of I_K. Similar relative inhibitions of I_K by dronedarone were obtained in young, sham, and PMI rats, even if I_K was less in sham than in young and further reduced in PMI rats. The EC₅₀ values were 0.78 and 0.85 µM in sham and PMI rats. Dronedarone induced a weak increase in the fast transient outward current, I_to. Time-to-peak and inactivation time constant of I_to were decreased by dronedarone that also induced a marked slowing of I_to recovery from inactivation. Similar effects were observed on the reduced I_to recorded in PMI rats. Holter monitoring study in control, unthetered animals showed that dronedarone had no proarrhythmic effect. On rats, which after myocardial infarction exhibited ventricular premature beats, dronedarone significantly decreased beat occurrence during the 7-day treatment; this effect was sustained for two more weeks. Thus, dronedarone exerts antiarrhythmic effects on PMI rat heart. Its effects are attributable for the most part to the inhibition of outward K⁺ currents and the increase in effective refractory period.